1. Field of the Invention
The oxygen and nitrogen substituted indoles described are useful in the treatment of AIDS.
2. Description of the Related Art
International Publication No. WO 87/01797 (U.S. Pat. No. 5,175,281) discloses compounds which can be visualized as steroid-piperazine-[substituted aromatic] or steroid-piperazine-[substituted heteroaromatic]. The steroid and piperazine being "connected" via the C.sub.17 side-chain of the steroid.
International Publication No. WO 88/08424 (U.S. Pat. No. 5,120,843) disclosed compounds which can be visualized as aromatic-connector-piperazine-[substituted aromatic] or aromatic-connector-piperazine-[substituted heteroaromatic], in particular see the compounds of formulas (I) and (III). None of those compounds were disclosed as having the utility set forth in this invention. In U.S. Pat. No. 5,120,843 it was disclosed that the compounds of formula (I) of International Publication No. WO 88/08424 were useful against AIDS.
An estimated one to one and one-half million people in the United States are infected with a human retrovirus, the human immunodeficiency virus type I (HIV-1) which is the etiological agent of acquired immunodeficiency syndrome, AIDS, see Science, 661-662 (1986). Of those infected, an estimated two hundred and fifty thousands people will develop AIDS in the next five years, see Science, 1352-1357 (1985). On Mar. 20, 1987, the FDA approved the use of the compound, AZT (zidovudine), to treat AIDS patients with a recent initial episode of pneumocystis carinii pneumonia, AIDS patients with conditions other than pneumocystis carinii pneumonia or patients infected with the virus with an absolute CD4 lymphocyte count of less than 200/mm.sup.3 in the peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication.
U.S. Pat. No. 4,724,232 claims a method of treating humans having acquired immunodeficiency syndrome utilizing 3'-azido-3'-deoxy-thymidine (azidothymidine, AZT).
Following the discovery of the anti-HIV activity of AZT, much effort has been focused on a wide variety of other dideoxynucleoside analogues in the search for superior agents. In the case of the 2',3'-dideoxy series, ddC and ddI have shown potent activity against HIV in vitro and have been evaluated in clinical trials, see Drug News & Perspectives, 5(3) 153-169 (1992) in particular page 160. The FDA has approved ddI for the treatment of HIV-1 infections in adults and pediatrics patients who are intolerant to, or whose health has significantly deteriorated while on, AZT treatment, see AIDS Research and Human Retroviruses, 8(6), 963-990, 1992 (1992) in particular page 966.
It is known in the art that certain antibiotics and polyanionic dyes inhibit retrovirus reverse transcriptase.
Many publications have reported the ability of various sulfated compounds to inhibit virus replication, including HIV.
Nature 343, 470 (1990) and Science 250, 1411 (1990) discloses potent benzodiazepin type reverse transcriptase inhibitors. The compounds of the present invention are not benzodiazepin type compounds.
U.S. Pat. Nos. 3,146,234 and 3,188,313 discloses compounds of the general formula
[substituted indol-2-yl]-(CH.sub.2).sub.n -[piperazinyl type]-[pyridinyl/pyrimidinyl]. The substituted indoles (I) of the present invention differ from the prior art compounds in that the substitution on the -.phi. ring of the indole is a different group than that of the group in U.S. Pat. No. 3,188,313.
VINITI, 3979-82 (1982) in Russian and Chem. Abst. 100(7) 51549b (1984) discloses a compound which can be represented as
5-methoxy [indol-2-yl]-CO-piperazinyl -[2-quinolinyl]which differs from the claimed compounds in that none of the claimed compounds have quinoline structure or any bicyclic structure attached to the piperazinyl moiety.
JP 01132579 (1987) discloses compounds which can be represented as
(optionally substituted)-[indol-2-yl]-CO-piperazinyl-(CH.sub.2).sub.n -[pyridinyl] which have very strong blood platelet agglutination inhibiting activity where n is 1-5 which differs from the claimed compounds in that the claimed compounds do not permit any linking group between the piperazinyl moiety and the phenyl or pyridinyl substituent.
Indian J. Chem. Sect. B, 17B(3), 246-9 (1979) and Indian J. Med. Res., 63(10), 1418-25 (1975) disclose compounds which can be represented as
(non-substituted)-[indol-2-yl]-CO-piperazinyl-(CH.sub.2).sub.n -[optionally substituted) phenyl]
The Indian J. Chem. Sect. B, 17B(3), 246-9 (1979) reported on p. 247 that none of the compounds showed any noteworthy (CNS) biological activity. The Indian J. Med. Res., 63(10), 1418-25 (1975) reported some of the compounds they prepared had anti-viral activity against Semliki forest virus (SFV) in mice. One compound, a dihydroisoquinolin was tested and found to be inactive against new castle disease virus in chick embryo. These compounds differ from the claimed compounds in that the claimed compounds require the indole group to be substituted.
International Publication EP 370 381 A2, published 5 May 90 discloses compounds which can be represented as EQU [heteroaryl]-CO-piperazinyl-[quinolinone]
where heteroaryl includes 2-indolyl which differ from the claimed compounds in that none of the claimed compounds have quinoline structure or any bicyclic structure attached to the piperazinyl moiety. The disclosed compounds possess cardiotonic and hypotensive activities and the capability of reducing the heart rate.
U.S. Pat. Nos. 5,032,598 and 5,215,989 discloses class III anti-arrhythmic compounds of the formula EQU R.sup.2 R.sup.3 Ar--[B]--X--Q--Y--R.sup.1
which if the appropriate substituents were selected generically encompasses some of the compounds of the present invention.
U.S. Pat. No. 3,472,855 and 3,562,278 disclose 3-indolinyl compounds which are useful as psychomotor depressants. The substituted indoles (I) of the present invention are useful for a totally different purpose, inhibition of HIV-RT and treatment of AIDS.
U.S. Pat. No. 3,362,956 discloses compounds of the general formula EQU [3-quinolyl]-(CH.sub.2).sub.n -[piperazinyl type]-[pyridinyl/phenyl].
The substituted indoles (I) of the present invention differ from the prior an compounds in that they do not include 3-quinolyl type compounds.
U.S. Pat. No. 3,472,854 discloses compounds of the general formula EQU [2-benzimidazolyl]-(CH.sub.2).sub.n -[piperazinyl type]-[pyridinyl/phenyl].
The substituted indoles (I) of the present invention differ from the prior an compounds in that they are indoles and not 2-benzimidazolyl type compounds.
U.S. Pat. No. 3,491,098 discloses compounds of the general formula EQU [4(5)-imidazolyl]-(CH.sub.2).sub.n -[piperazinyl type]-[pyridinyl/phenyl].
The substituted indoles (I) of the present invention differ from the prior an compounds in that they are indoles and not imidazolyl type compounds.
U.S. Pat. No. 3,511,841 discloses compounds of the general formula EQU [azaindolyl]-(CH.sub.2).sub.n -[piperazinyl type]-[pyridinyl/phenyl] EQU [azaindolyl]-CO-[piperazinyl type]-[pyridinyl/phenyl]
The substituted indoles (I) of the present invention differ from the prior an compounds in that they are they have substituted oxygen or substituted amino groups on the -.phi. portion of the indole and do not contain nitrogen in the ring.
U.S. Pat. No. 4,302,589 discloses 3-indolinyl compounds with a methyl group at the C.sub.2 position of the indole and an ethyl bridge between the indole and piperazine which are useful as anti-psychotics. The substituted indoles (I) of file present invention are useful for a totally different purpose, inhibition of HIV-RT and treatment of AIDS.
European patent publication 345,808 discloses 3-indolinyl-piperazinyl-[substituted 2-pyridinyl]compounds (example 66) which are useful anti-depressants. The substituted indoles (I) of the present invention are useful for a totally different purpose, inhibition of HIV-RT and treatment of AIDS.
International Publication No. WO 91/09849 (published Jul. 11, 1991) discloses diaromatic substituted heterocyclic compounds of the type [ARYL/HETEROARYL]-CONNECTOR-PIPERAZINE TYPE-ARYL/HETEROARYL useful in treating individuals infected with the HIV virus.
Proceedings of the National Academy of Sciences 88, 8806-10 (1991) discloses various bis(heteroaryl)piperazinyl non-nucleoside revere transcriptase inhibitors which potently and specifically block human immunodeficiency virus type 1 replication.
There are a number of other chemically unrelated compounds which have been reported to inhibit HIV and/or be useful in the treatment of AIDS.